The β-lactams (penicillins, cephalosporins, carbapenems and monobactams) are one of the most important and frequently used classes of antibiotics in medicine, in particular in the treatment of serious Gram-negative infections. Since the clinical introduction of penicillins and cephalosporins over 60 years ago, the emergence of β-lactamases, enzymes that hydrolyse the β-lactam ring that is involved in the cell-killing activity of these compounds, has been an ongoing clinical problem1. Antibiotic resistance has intensified medicinal chemistry efforts to broaden antibacterial spectrum while shielding the core β-lactam scaffold from β-lactamase-catalyzed hydrolysis. The result has been multiple generations of β-lactams with improved efficacy and tolerance to existing β-lactamases. However, pathogenic bacteria have in turn evolved further resistance mechanisms primarily by acquiring new or modified β-lactamases. This is typified by the emergence of extended spectrum β-lactamases that inactivate many of the latest generation cephalosporins and penicillins (but not carbapenems)2. Consequently, the past two decades have seen significant increases in the utilization of carbapenems such as imipenem and meropenem. Predictably, this increase in carbapenem consumption has been accompanied by the emergence of carbapenem-resistant Gram-negative bacteria3. In particular, carbapenem-resistant Enterobacteriaceae (CRE) is a growing crisis across the globe4 as witnessed by recent outbreaks in Chicago5 and British Columbia6.
Carbapenemases, β-lactamases that inactivate carbapenems, can be divided into two categories based on their mechanism of β-lactam ring hydrolysis. The first deploy an active site Serine residue that covalently attacks the β-lactam ring e.g. KPC and OXA-48 types7. The second are metallo-β-lactamases (MBLs) that use Zn2+ atoms to activate a nucleophilic water molecule that opens the ring e.g. Verona integron-encoded metallo-β-lactamase (VIM) and New Dehli metallo-β-lactamase (NDM) types8. Several inhibitors of Ser β-lactamases are clinically available as co-drugs where the inhibitor is formulated with a β-lactam antibiotic in order to overcome resistance (e.g. clavulanic acid-amoxicillin, tazobactam-piperacillin, sulbactam-ampicillin and the more recent Ser β-lactamase inhibitor avibactarn, which is in phase III clinical trials paired with various cephalosporins)9. Despite ongoing efforts10,11 there are no equivalent inhibitors for MBLs in the clinic for practical and technical reasons. First, until recently, MBL-derived CRE was not thought to be a major clinical problem and its rapid increase has outpaced MBL-inhibitor development. Second, the development of a single inhibitor to neutralise key clinically important MBL, such as VIM and NDM has been deemed too technically challenging, and overcoming in vivo toxicity associated with cross reactivity with human metallo-enzymes has been a concern. With the recent emergence of MBLs as a significant clinical threat, a potent and safe inhibitor of MBLs particularly against VIM and NDM would greatly benefit infectious disease management.
Aspergillomarasmines A and B are fungus-derived molecules that were discovered and reported in the early 1960s12,13. These molecules were evaluated in the 1980s as inhibitors of angiotensin-converting enzyme (ACE)14 and in the early 1990s as a pre-clinical candidate for the inhibition of activation of human endothelin15,16, a peptide that modulates blood vessel muscle contraction. This previous work demonstrated that AM-A was well-tolerated and had low toxicity in mice (LD50 159.8 mg/kg, i.v. compared to EDTA at 28.5 mg/kg) and had no effect on mean atrial blood pressure17. Another study reporting that AM-A has an LD50 of 250 mg/kg i.v. while AM-B has an LD50 of 660 mg/kg i.v. in rats14.
Lycomarasmine is also a fungal derived molecule that was first reported in 194718.